IMPACT OF NUTRITIONAL SUPPLEMENTATION ON ENVIRONMENTAL ENTERIC DYSFUNCTION (EED) IN CHILDREN LIVING IN RURAL AREAS: A SYSTEMATIC REVIEW

RACHMADI, Rizky Abi; ARIANI, Yulia; ALATAS, Fatima Safira

doi:10.1590/S0004-2803.24612023-159

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ORIGINAL ARTICLE/NUTRITION • Arq. Gastroenterol. 61 • 2024 • https://doi.org/10.1590/S0004-2803.24612023-159 copy

IMPACT OF NUTRITIONAL SUPPLEMENTATION ON ENVIRONMENTAL ENTERIC DYSFUNCTION (EED) IN CHILDREN LIVING IN RURAL AREAS: A SYSTEMATIC REVIEW

Impacto da suplementação nutricional na disfunção entérica ambiental (DEA) em crianças que vivem em áreas rurais: uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Background:

A staggering 99% of infant undernutrition mortality comes from Sub-Saharan Africa and South Asia. Despite multiple interventions focusing on nutrition adequacy, 2.7 million children worldwide remain associated with undernutrition-related mortality. The lack of impact from multiple interventions toward undernutrition reflects a strong reason to believe that EED is the missing link that sustains undernutrition in low-to-middle-income countries (LMICs). EED is a sub-clinical condition caused by repeated oral enteropathogenic and non-pathogenic fecal microbes exposure that causes intestinal villous malformation, multi-omics changes, chronic intestinal and systemic inflammation, and gut dysbiosis. EED impacts the absorptive capacity and the integrity of the gut, causing a cycle of undernutrition in children. There is currently no protocol for the diagnosis and treatment of EED, hence EED is widely believed to be highly prevalent and underdiagnosed in LMICs.

Objective:

To our knowledge, this is the first systematic review to study the impact of nutritional interventions on EED. Previous studies yielded inconsistent results, hence the synthesis of this information is essential in attaining a deeper understanding of EED to formulate new targets of intervention against child undernutrition.

Methods:

This systematic review is registered to PROSPERO (CRD42022363157) in accordance to PRISMA, using keywords referring to nutrient supplementation, EED, and child growth failure.

Results:

Eleven articles were eligible for review, comprising randomized controlled trials performed mainly in the African continent, with a total of 5689 healthy children eligible for analysis.

Conclusion:

The systematic review illustrates that nutritional interventions have a minimal impact on EED biomarkers and linear growth and reflects the importance of understanding better the mechanisms causing EED and its consequences. It appears that the anabolic contribution of nutrition intervention to child growth is negated by EED.

Keywords:
Gastrointestinal absorption; intestinal diseases; child malnutrition, dietary supplements; gastrointestinal microbiome; inflammation; environment, preventive medicine and public health

HIGHLIGHTS

•The lack of impact from multiple interventions toward undernutrition reflects a strong reason to believe that EED is the missing link that sustains undernutrition in low-to-middle-income countries (LMICs).

•There is currently no protocol for the diagnosis and treatment of EED, hence EED is widely believed to be highly prevalent and underdiagnosed in LMICs.

•To our knowledge, this is the first systematic review to study the impact of nutritional interventions on EED.

•The systematic review illustrates that nutritional interventions have a minimal impact on EED biomarkers and linear growth and reflects the importance of understanding better the mechanisms causing EED and its consequences.

Database	Search Terms	Hits
PUBMED	(Supplementation OR intervention) AND (environmental enteropathy OR environmental enteric dysfunction) AND (stunting OR malnutrition OR growth failure)	51
Cochrane	(Supplementation OR intervention) AND (environmental enteropathy OR environmental enteric dysfunction) AND (stunting OR malnutrition OR growth failure)	59
Total		110

Name of Study	Number of subjects	Age range	Study Design	Duration	Nutrition Intervention	Effect on EED	Effect on Linear Growth	Association Between EED and Linear Growth	Risk of Bias
Cheng et al.¹³13. Cheng WD, Wold KJ, Bollinger LB, Ordiz MI, Shulman RJ, Maleta KM, et al. Supplementation With Lactoferrin and Lysozyme Ameliorates Environmental Enteric Dysfunction: A Double-Blind, Randomized, Placebo-Controlled Trial. Am J Gastroenterol. 2019;114:671-8.	214	12-23 months	RCT	16 weeks	Lactoferrin and Lysozyme	Significant change of L% over 8 weeks when compared to the control group (0.23% vs 0.14% P=0.04). But not sustained after 16 weeks of study (0.16% vs 0.11% P=0.17)	After 16 weeks of intervention, there was no significant change in linear growth when compared to the control (0.028 mm/d and 0.030 mm/d respectively; P=0.12) l-		Low
Agapova et al.¹⁶16. Agapova SE, Stephenson KB, Divala O, Kaimila Y, Maleta KM, Thakwalakwa C, et al. Additional Common Bean in the Diet of Malawian Children Does Not Affect Linear Growth, but Reduces Intestinal Permeability. J Nutr. 2018;148:267-74.	331	12-23 months	RCT	48 weeks	Cowpea and common bean	The dual sugar absorption test, measuring %L and L:M, were not significantly different between the intervention and control groups after 48 weeks. However, only the common bean group had a significant effect estimate on %L (-0.073396, SD 0.029887; P=0.0073)	Change in LAZ score after 48 weeks of intervention was not significant compared to the control group. The changes in LAZ score was 0.14±0.49, -0.11±0.54 (P=0.67) and -0.07±0.51 (P=0.31) in the control, cowpea and common bean group respectively after 48 weeks	The parameter was not studied	Low
Wessells et al.¹⁰10. Wessells KR, Hinnouho GM, Barffour MA, Arnold CD, Kounnavong S, Kewcharoenwong C, et al. Impact of Daily Preventive Zinc or Therapeutic Zinc Supplementation for Diarrhea on Plasma Biomarkers of Environmental Enteric Dysfunction among Rural Laotian Children: A Randomized Controlled Trial. Am J Trop Med Hyg. 2020;102:415-26.	359	6-23 months	RCT	36 weeks	Zinc and MNP	The intervention after 36 weeks did not have a significant effect estimate on citrulline, kynurenine, tryptophan and KT ratio	After 36 weeks, there was no significant difference of LAZ score between the intervention and control groups. The LAZ score at the end of the study were: preventive zinc group −1.93±0.97, micronutrient powder group −1.94±1.00, theraupetic zinc group −1.95±1.02 and control group −1.93±1.00 (P=0.58)  obtained from parent trial (Balffour 2019)	Citrulline, Kynurenine, Tryptophan and KT ratio was not associated with changes in LAZ score after 36 weeks	Low
Hinnouho et al¹²12. Hinnouho GM, Wessells KR, Barffour MA, Sayasone S, Arnold CD, Kounnavong S, et al. Impact of Different Strategies for Delivering Supplemental Zinc on Selected Fecal Markers of Environmental Enteric Dysfunction among Young Laotian Children: A Randomized Controlled Trial. Am J Trop Med Hyg. 2020;103:1416-26.	720	6-23 months	RCT	36 weeks	Zinc and MNP	The intervention had no significant impact on endline MPO, NEO and CAL after 36 weeks	No data	MPO, but not NEO and CAL, was associated with change in LAZ score after 16-20 weeks ((−0.029, (−0.054, −0.003); P= 0.027)). However, after 32-40 weeks of intervention, MPO, NEO and CAL were not associated with the change in LAZ score	Low
Bierut et al.²⁰20. Bierut T, Duckworth L, Grabowsky M, Ordiz MI, Laury ML, Callaghan-Gillespie M, et al. The effect of bovine colostrum/egg supplementation compared with corn/soy flour in young Malawian children: a randomized, controlled clinical trial. Am J Clin Nutr. 2021;113:420-7.	275	9 months	RCT	36 weeks	Bovine Colostrum and Egg	Using L%<0.20 as a cut-off for EED, after 36 months of intervention, the study found resolution of EED in 50% (10/20 subjects) of patients, while in the control group EED resolution was found in 13.3% (2/15 subjects) of patients (P<0.05)	After 36 weeks of intervention, there was a significant difference of change in LAZ score between the intervention and control group (0.12 z-scores, P=0.0011). However, the study observed the two groups until 5 months post-intervention, and at that point the difference of change of LAZ score between the two groups was no longer significant. On the other hand, 5 months post intervention, the prevalence of stunting in the intervention group was significantly smaller (47 ((35)); RR 0.70; CI95%=0.52-0.94; P=0.018)) compared to the control group (62 ((49))	The parameter was not studied	Low
Ryan et al.¹¹11. Ryan KN, Stephenson KB, Trehan I, Shulman RJ, Thakwalakwa C, Murray E, et al. Zinc or Albendazole Attenuates the Progression of Environmental Enteropathy: A Randomized Controlled Trial. CGH. 2014;12:1507-1513.e1.	222	12-36 months	RCT	48 days	Zinc	Change in L:M and the prevalence of subjects with L:M >0.30 was significantly lower in the zinc group compared to placebo (P<0.02 and P<0.04 respectively). However, there was no significant difference between groups for mannitol excretion after the intervention	There was no significant change in length (cm) between groups after 48 days. The change in length was 1.1±0.9 in the zinc group and 1.1±1.6 in the placebo group	The parameter was not studied	Low
Lin et al.¹⁸18. Lin A, Ali S, Arnold BF, Rahman MZ, Alauddin M, Grembi J, et al. Effects of Water, Sanitation, Handwashing, and Nutritional Interventions on Environmental Enteric Dysfunction in Young Children: A Cluster-randomized, Controlled Trial in Rural Bangladesh. Clin Infect Dis. 2020;70:738-47.	1783	recruited since birth	Cluster RCT	18 months	SQ-LNS	NEO was lower in the intervention group at 3 months and 14 months. However, by 28 months there were no differences in NEO in between all groups	Linear growth was an assessed parameter in the parent trial; however, the results are not yet published	Association between Linear growth and EED was an assessed parameter in the parent trial, however, the results are not yet published	Low
						At 3 and 14 months, there was no difference in MPO in between groups, however by 28 months, MPO was higher in the WASH group and nutrition group compared to controls
						At 3 months, Lactulose was lower in all intervention groups compared to the control group. However, at 14 months there were no differences in all groups. And at 28 months, lactulose was higher in the WASH group compared to controls
						At 3 months, mannitol was lower in all intervention groups compared to control groups. However, at 14 and s8 months, there were no difference in mannitol in all groups
						L:M at 3 months was no different in all groups. At 28 months, L:M was higher in all intervention groups compared to control group
						There was no difference in AAT in all groups at 3, 14 and 28 months
Smith et al.¹⁴14. Smith HE, Ryan KN, Stephenson KB, Westcott C, Thakwalakwa C, Maleta K, et al. Multiple Micronutrient Supplementation Transiently Ameliorates Environmental Enteropathy in Malawian Children Aged 12-35 Months in a Randomized Controlled Clinical Trial. J Nutr. 2014;144:2059-65.	230	12-35 months	RCT	24 weeks	MNP and Fish Oil	L:M after 24 weeks significantly improved from baseline in intervention groups and control group (P<0.05), however there was no significant difference between the intervention groups and the control group. In terms of L% excreted. there was no significant difference between groups after 24 weeks	The parameter was not studied	The parameter was not studied	Low
Gough et al.¹⁷17. Gough EK, Moulton LH, Mutasa K, Ntozini R, Stoltzfus RJ, Majo FD, et al. Effects of improved water, sanitation, and hygiene and improved complementary feeding on environmental enteric dysfunction in children in rural Zimbabwe: A cluster-randomized controlled trial. PLoS Negl Trop Dis. 2020;14:e0007963.	1169	recruited since birth	Cluster RCT	18 months	SQ-LNS	There was no consistent evidence that the intervention interacted with any biomarker in this study	The parameter was not studied	The parameter was not studied	Low
						Stool biomarkers of inflammation decreased at the end of the study, MPO was consistent from months 1-6 7518 ng/mL (95%CI:7014-8059) then rapidly declined to 2825ng/mL (95%CI:2669-2991) at 18 months. NEO increased in the first six months (from 980 nmol/L (95%CI:908-1057) to 1283 nmol/L (95%CI:1230-1337)) then decreased at 18 months to 383 nmol/L (95%CI:362-407)
						Intestinal damage biomarkers had no discernible pattern. Stool REG-1β increased in the first 12 months from 40.6μg/mL (95%CI:36.4-45.1) to 154.6 μg/mL (95%CI:145.5-164.2) then decreased to 132.9μg/mL (95%CI:123.1-143.6). Plasma citrulline increased from 2744 ng/mL (95%CI:2658-2834) at month 6 to 3150 ng/mL (95%CI:3075-3227) by 12 months. I-FABP had a U-shaped pattern, starting with a decline in the first 6 months from 1031 pg/mL (95%CI:993-1021) to 913 pg/mL (95%CI:892-934, then increased to 1198 pg/mL (95%CI:1160-1237) at 18 months
						Intestinal permeability biomarkers overall decreased during the 18 month follow-up, showed by AAT from 0.47 mg/mL (95%CI:0.44-0.51) to 0.24 mg/mL (95%CI:0.22-0.25) at 18 months and urinary LM ratio declined from 0.84 (95%CI:0.71-0.8) at 6 months to 0.49 (95%CI:0.43,0.53) at 18 month
						Plasma systemic inflammation markers showed opposite patterns, where CRP steadily increased rom 0.63mg/L (95%CI:0.55-0.71) to 1.28mg/L (95%CI:1.14-1.43) in 18 months, KTR declined from 64.8 (95%CI: 62.2,67.6) at 1 month to 44.9 (95%CI: 43.6,46.3) between 6-12 months
						Marker of microbial translocation, Soluble CD14 increased from 769,192 pg/mL (95%CI: 741,069-798,383) to 1,334,175 pg/mL (95%CI: 1,292,950-1,3767,16) in 18 months
						Meanwhile IGF-1 decreased from 27.1 ng/mL (26.0-28.2) to 17.9 ng/mL at 12 months (17.4-18.5)
Vilander et al.²¹21. Vilander AC, Hess A, Abdo Z, Ibrahim H, Doumbia L, Douyon S, et al. A Randomized Controlled Trial of Dietary Rice Bran Intake on Microbiota Diversity, Enteric Dysfunction, and Fecal Secretory IgA in Malian and Nicaraguan Infants. J Nutr. 2022;152:1792-800.	95	6 months	RCT	6 months	Rice bran	There was no significant difference of total fecal sIgA between rice bran and control groups after intervention. Total fecal sIgA is significantly correlated with NEO, AAT, CAL and MPO over a 6 month period of study. Malian rice bran groups observed significantly decreased EED scores compared to control group, but this was not observed in the Nicaragua rice-bran group. NEO, AAT, CAL and MPO were not correlated with EED scores	The parameter was not studied	The parameter was not studied	Low
Stephenson et al.¹⁵15. Stephenson KB, Agapova SE, Divala O, Kaimila Y, Maleta KM, Thakwalakwa C, et al. Complementary feeding with cowpea reduces growth faltering in rural Malawian infants: a blind, randomized controlled clinical trial. Am J Clin Nutr. 2017;106:1500-7.	291	6 months	RCT	6 months	Cowpea and common bean	After 6 months of intervention, there was no significant difference of L:M, Lactulose excretion and mannitol secretion compared to the control group	The cowpea group observed a significant decrease in LAZ score ((-0.14±0.52 (111); P=0.048) compared to common bean and placebo in the first 3 months of the study. However no significant change of LAZ score was observed in all groups after 6 months of intervention. At the end of the study, the change of LAZ score was -0.13±0.68 (103), -0.17±0.66 (106), -0.14±0.60 (98) for cowpea, common bean and the control group respectively (P>0.05)	The parameter was not studied	Low

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[1] Corresponding author: Rizky Abi Rachmadi. E-mail: rizkyabirachmadi@gmail.com